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JP4044190B2 - Method for producing drug-releasing coating - Google Patents

Method for producing drug-releasing coating Download PDF

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Publication number
JP4044190B2
JP4044190B2 JP36511297A JP36511297A JP4044190B2 JP 4044190 B2 JP4044190 B2 JP 4044190B2 JP 36511297 A JP36511297 A JP 36511297A JP 36511297 A JP36511297 A JP 36511297A JP 4044190 B2 JP4044190 B2 JP 4044190B2
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polymer
solvent
drug
coating
spray
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JPH10192413A (en
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ニ・ディン
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ボストン・サイエンティフィク・サイムド・インコーポレーテッド
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0005—Use of materials characterised by their function or physical properties
    • A61L33/0011—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6957—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a device or a kit, e.g. stents or microdevices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/047—Other specific proteins or polypeptides not covered by A61L31/044 - A61L31/046
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B13/00—Machines or plants for applying liquids or other fluent materials to surfaces of objects or other work by spraying, not covered by groups B05B1/00 - B05B11/00
    • B05B13/02—Means for supporting work; Arrangement or mounting of spray heads; Adaptation or arrangement of means for feeding work
    • B05B13/04—Means for supporting work; Arrangement or mounting of spray heads; Adaptation or arrangement of means for feeding work the spray heads being moved during spraying operation
    • B05B13/0442—Installation or apparatus for applying liquid or other fluent material to separate articles rotated during spraying operation

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Chemical & Material Sciences (AREA)
  • Vascular Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Materials Engineering (AREA)
  • Hematology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Materials For Medical Uses (AREA)
  • Media Introduction/Drainage Providing Device (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)

Description

【０００１】
【発明の属する技術分野】
本発明は一般に、体内へ挿入または移植される医療器具のための薬物放出性被覆に関するものである。更に具体的には、本発明は、ポリマー系を形成するようにポリマーを第一の溶媒（溶媒Ａ）に溶解し、そして薬物系を形成するように薬物を第二の溶媒（溶媒Ｂ）に溶解する、医療器具へ薬物放出性被覆を適用する方法である。
【０００２】
【従来の技術及び発明が解決しようとする課題】
従来の方法においては、溶媒中に薬物とポリマーの混合物を含む組成物を器具に適用して薬物とポリマーの実質的に均一な層（すなわち実質的に均一にポリマー中へ薬物を分散した層）を形成していた。用いるポリマーや薬物の種類に応じて、これら２つの成分に共通な溶媒を見いだすことは困難であった。薬物とポリマーに共通の溶媒が存在しないときは、薬物を微細化して小粒子とし、ポリマー溶液に懸濁する試みが行われてきた。しかしながら微細化には時間がかかり、薬物に望まれる治療的特性が失われることもあった。したがって、薬物とポリマーの両方を容易に溶液として、医療器具の薬物放出性被覆を得る方法が必要とされている。また、共通の溶液または懸濁液の中で薬物とポリマーが結合することなしに、薬物／ポリマー被覆を適用する方法も必要である。
【０００３】
【課題を解決するための手段及び発明の実施の形態】
以下に述べる方法は、一般的には移植可能なプロテーゼ（人工器官）、特にバルーン拡張可能なステントや自己拡張性ステントのような拡張可能プロテーゼに適用するものである。本発明により被覆されたステントは、例えば塑性変形可能または自己拡張性である。ある実施態様において、この方法は薬物をステントに適用する前に微細化する必要がない。他の実施態様においては、薬物粒子を用いることもできる。本発明はまた、ポリマーと薬物に共通な相溶性の溶媒がない場合にも用いることができる。
【０００４】
本発明は、広くは、薬物が実質的に均一にポリマー中に分布しているような薬物及びポリマー含有の薬物放出性被覆を適用する方法に関するものである。ポリマーを第一の溶媒（溶媒Ａ）に溶解し、生物学的活性物質を実質的に含まない（たとえばポリマーの約１重量％より少ない）ポリマー系を形成でき、また薬物を第二の溶媒（溶媒Ｂ）に溶解して、ポリマーを実質的に含まない（たとえば薬物の約１重量％より少ない）薬物系を形成することができる。溶媒Ｂは、溶媒Ａと同一であっても異なっていてもよい。薬物がポリマー溶液に極めて溶けにくく、薬物とポリマーの双方に共通の溶媒は見いだせない場合は、一般に異なった溶媒が用いられる。ポリマー系と薬物系を医療器具に別個に適用することにより、本方法はポリマーと薬物の複合体、すなわちポリマーの網目全体に薬物が分布している状態を形成する。そのような複合体は実質的に均一であり得る。本発明の方法では、薬物とポリマーの複合体をつくるために薬物をポリマーとを混合する前に微細化する必要がない。この方法は薬物とポリマーの複合体を含む被覆または層を提供するものであるが、器具に被覆を適用する前に薬物とポリマーを１つの溶液の中で混合する必要をなくすものである。
【０００５】
被覆は、ポリマー系と薬物系を別々に噴霧することにより器具、特にステントに適用することができる。ステントを被覆する方法は、米国特許出願番号第08/424,884；08/526,273；及び08/663,490号に開示されている。これらの文献は、すべての目的のためにそれら全体を参考として本明細書に包含するものとする。本発明の被覆は以下に詳細に説明するように、ポリマーと薬物系を逐次的または同時に噴霧することにより達成することができる。
【０００６】
被覆を噴霧によって適用するかわりに、被覆はまた浸漬によっても医療器具上に配設することができる。この被覆適用方法は、噴霧被覆ができないような器具には特に有用であう。そのような器具は移植ステント（stent graft）の内腔（inner lumen）を含むが、これに限定されるものではない。被覆はさらに、噴霧と浸漬を併用して適用してもよい。
【０００７】
所望の被覆の厚みに応じて、多工程被覆を適用してもよい。溶媒の揮発性に応じて、噴霧若しくは浸漬工程中に待ち時間が必要なこともあり、または加熱銃（ヒート・ガン）、加熱ランプ若しくは加熱室によって熱をかけて溶媒の蒸発を促進してもよい。
【０００８】
ある実施態様においては、薬物を溶媒Ｂに溶解する必要がない。微粒子を溶媒中で混合、好ましくは懸濁し、そして被覆をここに記載のようにして適用することができる。場合によっては、３つまたはそれ以上の系を用いることができる。例えば、もし第三の系の溶媒が、ポリマーマトリックス、又は薬物のような第二の溶離可能物質を含有する第三の噴霧もしくは浸漬系と相溶性であれば、純粋な溶媒ＡまたはＢを含有する第三の噴霧または浸漬系は被覆表面を平滑にすることができる。溶媒（これは溶媒ＡやＢと同じでも異なってもよい）中のポリエチレグリコール、砂糖、塩を、ステントに適用することができる。２つ又はそれ以上の薬物を用いて得られた薬物放出体は、個々の薬物を同時にまたは逐次的に放出することができる。
【０００９】
本発明による適当な順序は、ポリマー溶液の適用、薬物溶液の適用、そして純粋な溶媒の適用であり得る。またはこの順序は、ポリマー溶液の噴霧もしくは浸漬による適用、溶媒の適用、そして薬物の溶液もしくは懸濁液の適用であってもよい。またはこの順序は、３つの平行して行われる噴霧であってもよい。各々の操作での回数は、１／２、１回、２回またはそれより多くてもよい。当業者は、本発明の概念を逸脱することなく２つ又はそれより多い被覆系のために被覆順序と順番のための多くの組み合わせを見いだすであろう。被覆系は、種々の組み合わせを達成するために手作業によっても又は自動化によってもよい。
【００１０】
本発明に適当なポリマーは、分解せずそして組織拒絶反応を最小化するような疎水性の生体安定性(biostable)エラストマー材料であることが好ましい。さらにこの材料は、ステントの移植部位に近い組織によってカプセル化されるようなものであることが望ましい。そのような被覆のために適切なポリマーとしては、シリコーン（例えばポリシロキサンや置換ポリシロキサン）、ポリウレタン（ポリカーボネートウレタンを含む）、一般の熱可塑性エラストマー、エチレンビニルアセテート共重合体、ポリオレフィンエラストマー、ＥＰＤＭゴム及びポリアミドエラストマーなどがある。上記の材料は、本発明で意図する環境に関しては疎水性であると考えられる。
【００１１】
本発明で用いるのに適した他のポリマーの非限定的な例は、例えば、ポリ乳酸、ポリグリコール酸、ポリカプロラクトン、ポリ乳酸−ポリエチレンオキサイド共重合体、セルロースなどの生体吸収性のポリマーを含む。本発明に用いるのに適した他の非限定的なポリマーの例には、アクリル酸とその誘導体、ナイロン及びポリエステルのような生体安定性プラスティック材料もまた含まれる。
【００１２】
本発明に用いられる薬物の非限定的な例は、アンチトロボティクス（Antithrobotics）、抗凝固剤、抗血小板剤、血栓溶解剤、抗増殖剤、抗炎症剤、過形成阻害剤、平滑筋細胞阻害剤、抗生物質、成長因子、成長因子阻害剤、細胞接着阻害剤、細胞接着促進剤および内皮細胞再生を含めた健常新血管内膜組織形成促進剤を包含する。陽性作用は、特定の細胞（たとえば平滑筋細胞）または組織形成（たとえば繊維筋肉組織）の阻害、異なる細胞の移動（たとえば内皮細胞）や組織形成（新内膜組織）の活性化に由来する。
【００１３】
本発明で用いる薬物は微細化してもよいし、しなくてもよい。薬物を微細化しないときは、薬物の粒子径は約１０μｍ以上であり得る。薬物を微小化したときは、薬物の粒子径は、好ましくは５〜１２μｍであり、更に好ましくは約５μｍである。
【００１４】
本発明に適当な器具には、カテーテル、シャント（shunts）、ステント（例えば自己拡張可能またはバルーン拡張可能な血管または非血管ステント）、心臓弁、グラフト（graft）及び人工臓器や人工装具が、非限定的に包含される。これらの器具はポリマー、金属またはセラミックの表面を有していてもよい。
【００１５】
ステント、特に図１０に示すような編製のシャントを構築するのに好ましい材料は、ステンレス鋼、タンタル、チタン合金たとえばニチノール（ニッケルとチタンの熱記憶合金材料）、米国特許第5,630,840号に記載のようなＤＦＴ材料並びにエルジロイ（Elgiloy）及びフィノックス（Phynox）のようなコバルト−クロム−ニッケル合金といった金属類を含む。生体吸収性材料もまた、ポリ乳酸のようにステント構造の形成に用いることができる。構築のさらに詳細やこれ以外のステント自体の詳細は、米国特許第4,655,771号、第4,954,126号及び第5,061,275号に記載されており、これらはそのすべてが参考にためにこの明細書に含まれるものとする。
【００１６】
本発明に使用可能な溶媒は、好ましくは、ポリマーや薬物と混合したときに相溶性のものである。例えば、ポリマーは好ましくは、混合したときにその溶媒中に充分に溶解可能であり、薬物は好ましくは、混合したときにその溶媒中に充分に溶解可能であることである。しかしながら、本発明のいくつかの実施態様は、溶媒中で混合された、例えばヘパリンのような微粒子薬物をも包含する。薬物が微粒子形態のときは、薬物を好ましくは溶媒中に懸濁する。本発明に使用可能な溶媒の非限定的な例は、テトラヒドロフラン、メタノール、メチルエチルケトン、クロロホルム、メチレンクロリド、アセトニトリル及び水を含む。
【００１７】
【実施例】
以下の実施例は、被覆が、医療器具に噴霧被覆（比較例および実施例１〜３）または浸漬被覆（実施例４〜６）によって適用される本発明の実施態様を記載したものである。
【００１８】
（比較例）
シリコーンとキシレンの混合物（約３４％固形分重量；Applied Silicone Corporation）を秤量し、固形シリコーン含量を計算した。Ｗdex／Ｗsilicone solid＝０．１）の比を製造に用いた。ここで”ｄｅｘ”又は”ＤＥＸ”とはデキサメタゾン（Upjohn；アメリカ薬局方デキサメタゾン；ＣＡＳ登録番号50-02-2）である。用いたテトラヒドロフラン（ＴＨＦ）（ＨＬＰＣ純度；Aldrich又はEM Science）の容量は、固形シリコーンの重量を２０倍して測定した。ＤＥＸをまずＴＨＦに溶解し、次いでシリコーン−キシレン混合物へ移した。架橋剤を加え、そして溶液をよく混合した。編製したステントを、均一溶液で何度も噴霧して拡張状態のステントに被覆した。被覆したステントを対流オーブンへ移し、１５０℃で４５分間処理した。次いでアメリカ特許出願08/841,747号に記載の方法でアルゴンガスプラズマで処理した。その結果を図１、４及び５に示す。図１と４はストレスをかけてない状態、すなわちステントを拡張や収縮する以前の状態の被覆の写真である。図５は、被覆ステントを機械的にストレスをかけた後の状態、すなわちステントを収縮および拡張した後の状態の被覆の写真である。
【００１９】
（実施例１）
ＴＨＦ中５％（ｗ／ｗ）の固形シリコーン溶液を、必要なＴＨＦと架橋剤をシリコーン混合物の中へ加えて製造した。これとは別に、ＴＨＦ中０．５％シリコーン溶液を、ＤＥＸ含有のビーカーの中へＴＨＦを添加して製造した。Ｗdex／Ｗsilicone solidの比は０．１であった。バジャー(badger)の１５０−４噴霧系を、２つの異なる溶液を入れた２つの貯留器と共に用いた。拡張状態のステントの被覆を、シリコーン溶液の１サイクルの噴霧、短い待ち時間（約３０秒）及びＤＥＸの１サイクルの噴霧、短い待ち時間（約３０秒）、そして噴霧操作の繰り返しによって完結した。一番最後の噴霧サイクルはシリコーン溶液であった。３０ミクロンの被覆厚みを得るために、各々の約３０サイクルを適用した。用いた噴霧サイクルの数は、溶液の粘度、液滴のサイズおよび流速に依存した。次いで被覆したステントを対流オーブンへ移し、１５０℃で４５分間処理した。さらにアルゴンガスプラズマで処理した。その結果を図２、６及び７に示す。図２と６は非ストレス状態での被覆の写真である。図７は、被覆されたステントが機械的にストレスを受けた後の被覆の写真である。
【００２０】
（実施例２）
この実施例のものを製造するのに用いた方法は、シリコーンに対し貧溶媒であるメタノールにＤＥＸを溶解した以外は、実施例１で用いた方法と類似のものである。製造中はＷdex／Ｗsilicone solidの比を０．１に保った。結果を図３、８及び９に示す。図３と８は、非ストレス状態での被覆の写真である。図９は、被覆ステントを機械的にストレスにかけた、すなわち拡張し収縮した後の被覆の写真である。
【００２１】
（実施例３）
比較例、実施例１、及び実施例２で製造した被覆ステントを２ｃｍの部分に切断し、ポリエチレングリコール（分子量＝４００、Aldorich）と水の混合物（４０／６０、ｖ／ｖ）１００ｍｌの中へ入れた。溶液をサンプリングするごとにこの溶液を頻繁に変えた。ＤＥＸ濃度を、島津製作所の高速液体クロマトグラフィー機器を用い２５４ｎｍの波長でＵＶ検出器で操作して分析した。分析にはＣ−８カラムを用いた。表１と図１５は、被覆ステントの１カ月にわたるＤＥＸ放出データを示すものである。比較例、実施例１および実施例２の３つの製品はすべて薬物の放出を延長させ、そして類似の放出プロフィールを有していた。
【００２２】
【表１】

Figure 0004044190
【００２３】
噴霧被覆を含む本発明の実施態様は、図１１と１２に順を追って説明されている。薬物放出性被覆の被覆装置２は、ステント回転装置４と噴霧装置６を具備する。
【００２４】
典型的には鰐口クランプにより、支持部材２４’、２４”の両端で挟むことにより、ステント回転装置４上にステント８をマウントする。好ましくはステント８は、少なくとも部分的に拡張されるか十分に拡張された状態で挟まれて、その内部が、噴霧被覆がステント８の外部と内部の表面に接着するような空間を残しておく。棒部材２４’、２４”はステント８の内部を横切らない。モーター１０は棒部材２４’、２４”を回転させることによりステント８を回転させる。支持棒１２は、ステント回転装置４を支持している。
【００２５】
噴霧装置６は、第一の噴霧缶１６と第二の缶１８がマウントされている構造支持体１４をもっている。第一の噴霧缶１６は第一の噴霧ディスペンサー２０に連通し、第二の噴霧缶１６は第二の噴霧ディスペンサー２２に連通している。ガス供給手段２６、２８は噴霧装置に接続されて、ポリマー溶液と薬物溶液を推進させる。
【００２６】
第一と第二の噴霧缶１６、１８は、トラック（図示してない）上の構造支持体１４上にマウントすることができ、長尺方向に前後に並進運動可能とすることができる。簡単な場合には、手を支持体１４として作動させることができる。この実施態様において、缶１６、１８は、互いに所定の間隔で固定され、共に等距離を移動する。図１１の白抜きの矢印は、左方向への運動する前の缶１６、１８を示す。ひと度噴霧ディスペンサー２０、２２がステント８に対向すると噴霧が開始される。図１１の黒の矢印は、右方向へ戻り始め、再びディスペンサー２０、２２がステントに対向して噴霧を開始する缶１６、１８を示す。この動作は、所望に応じて何度も反復することができる。
【００２７】
この実施態様において、第一の噴霧缶１６は、溶媒中にポリマーを含有するが薬物を含有しない状態であり得るし、一方では、第二の噴霧缶１８は、溶媒中に薬物を含有するがポリマーを含有しない状態であり得るし、またその反対にもなり得る。
【００２８】
図１３と１４は、本発明の他の実施態様を逐次説明するものである。この実施態様における参照番号は、図１１および１２で示した実施態様で用いたものと同じ意味を有している。
【００２９】
第一の及び第二の噴霧缶１６、１８は、２つのトラック（図示してない）上の構造支持体１４上にマウント可能で、長尺方向に並進運動が可能とすることができる。この実施態様では、缶１６、１８は互いに独立して並進運動が可能である。図１３において黒い矢印は、左方向へ運動してステントを噴霧する第一の缶１６を示し、白抜きの矢印は、静止位置において左方向へ運動するために待機中の第二の缶１８を示す。第一の缶１６は左への運動を続け、次いでステントを越えて停止し休止位置（図示してない）となる。次に図１４に示すように、第二の缶１８は、左へ動いてステントを噴霧し、それからステントの左で休止する。その後、第一の缶１６は右へ動き、第二の缶１８が続き、そして所望に応じてこの行程は反復される。
【００３０】
本発明による他の方法は、第一の缶１６が前後に並進運動する間は第二の缶１８がステントを越えた位置で休止し、次いで、第二の缶が前後に並進運動する間は第一の缶がスタントを越えた位置で休止する行程を含んでいる。他の非限定的変形例は、同時に運動するが互いに離れている缶１６と１８を具備すること、又は、噴霧中は十字に交差する缶１６と１８を具備することを含む。
【００３１】
噴霧被覆に加えて、本発明の被覆は、１）第一の溶媒に溶解したポリマー及び２）第二の溶媒に溶解した薬物の中へ、医療器具を浸漬することにより適用することができる。器具は、所望の厚みの被覆が得られるまで反復してポリマーと薬物の溶液に浸漬することができる。一般に、溶媒のポリマー及び薬物に対する相対的溶解性(solvability)に応じて、連続する浸漬工程において、薬物は再結晶化または再分布され、ポリマーは収縮し膨潤するものである。器具における被覆の均一性を確実にするために、ある種の工程を採用した。これらの工程は以下を含むが、これには限定されない。すなわち、低粘度係数の溶媒を選択すること、内部ポリマー層は膨潤するが容易には溶解しないようにポリマーをその絡み合い分子量以上に選択すること、各々の浸漬後に被覆を送風乾燥すること、器具を水平に被覆すること、乾燥中は器具を回転すること、及び、被覆時間を短縮することである。
【００３２】
以下の実施例は、浸漬による製造が行われる本発明の実施態様を示すものである。
【００３３】
（実施例４）
３５％の固形物を含むシリコーン分散液（Applied Silicone Corporation）（#40000）（１５グラム）を秤量した。デキサメタゾン（ＤＥＸ）（Upjohn、ロット#719kT）（０．５２グラム）をテトラヒドロフラン（ＴＨＦ）１５ｍｌに溶解した。薬物溶液をシリコーン分散液に加え、均一溶液になるまで攪拌した。
【００３４】
ステントグラフト（実施例４ａ）をこの溶液に浸漬し、水平位置で通気乾燥した。このサンプルの被覆重量は１０．８ｍｇ／ｃｍ2であった。重力のために、被覆は凹凸になった。さらに均一の被覆を得るために、溶液に浸漬後、第二のステントグラフト（実施例４ｂ）を、風乾しながら水平に回転させた。このサンプルの被覆重量は１３．５ｍｇ／ｃｍ2であった。室温で約１．５時間放置したあと、被覆サンプルをオーブンで１５０℃で１時間処理した。
【００３５】
グラフトを２ｃｍの小片に切断し、その放出速度をポリエチレングリコール（ＰＥＧ）（分子量＝４００；J.T.Baker）の２５／７５ｖ／ｖ水溶液に浸漬して調べた。溶液を定期的にサンプリングし、新鮮な溶液と交換した。放出されるＤＥＸの量を、２５４ｎｍの波長でＵＶ検出器を用い１ｍｌ／ｍｉｎの流速でアセトニトリル／水（１：１、ｖ／ｖ）の移動相でＣ８カラム（Phase Separation Ltd）を用いて、島津製作所の高速液体クロマトグラフィー（ＨＰＬＣ）により定量した。これら２つのサンプルの放出速度を表２に示す。これらのデータは、被覆サンプルは薬物の放出が延長されていることを示している（図１６参照）。
【００３６】
【表２】
Figure 0004044190
【００３７】
ＴＨＦ中に４％のシリコーンを含有するシリコーン分散液を作製した。またＴＨＦ中１０％のＤＥＸ溶液も作製した。ステントグラフトをまずシリコーン溶液に浸漬し、少なくとも１分間回転させながら乾燥させた。このステントをＤＥＸ／ＴＨＦ溶液に浸漬し、少なくとも１分間回転してステントを乾燥させた。この浸漬と乾燥の操作を約２０回反復した。最後の浸漬はシリコーン溶液の中であった。室温に約１．５時間放置した後、被覆されたサンプルを１５０℃で１時間オーブンの中で処理した。
【００３８】
実施例４ａと４ｂのステントと同様、このサンプルもまた２ｃｍの小片に切断し、実施例４ａ及び４ｂで用いた方法により放出速度を調べた。実施例５における放出速度は、表２と図１６に示した。これらのデータは、被覆サンプルは薬物放出が延長されていることを示している。
【００３９】
（実施例６）
実施例５のシリコーン分散液を作製した。また、シリコーンの貧溶媒であり従ってシリコーンとは相溶しないメタノール（ＭｅＯＨ）中のＤＥＸの１０％溶液も作製した。実施例５を作製するのに用いた方法によって、ステントグラフトを被覆した。このサンプルを２ｃｍの小片に切断し、放出速度を実施例４ａと４ｂで用いた方法によって調べた。実施例６の放出速度を表２に示す。これらのデータは、被覆サンプルは薬物放出が延長されていることを示すが、このサンプルは、実施例４ａ、４ｂ及び５のものに比べて、初期薬物溶離が速かった（図１６参照）。
【００４０】
ここに記載したものは例示の目的のためのみであって、限定の目的のためではない。記載した実施態様について変更や修正を行うことができ、それらも本発明の範囲内にある。さらに、明白な変更、修正または変形もまた当業者により行われるであろう。
【図面の簡単な説明】
【図１】 比較例の被覆ステントを示す走査電子顕微鏡写真である。
【図２】 実施例１の被覆ステントを示す走査電子顕微鏡写真である。
【図３】 実施例２の被覆ステントを示す走査電子顕微鏡写真である。
【図４】 非ストレス状態の比較例の被覆ステントを示す走査電子顕微鏡写真である。
【図５】 ストレス後の状態の比較例の被覆ステントを示す走査電子顕微鏡写真である。
【図６】 非ストレス状態の実施例１の被覆ステントを示す走査電子顕微鏡写真である。
【図７】 ストレス後の状態の実施例１の被覆ステントを示す走査電子顕微鏡写真である。
【図８】 非ストレス状態の実施例２の被覆ステントを示す走査電子顕微鏡写真である。
【図９】 ストレス後の状態の実施例２の被覆ステントを示す走査電子顕微鏡写真である。
【図１０】 被覆前のステントの一例を示す斜視図である。
【図１１】 本発明の被覆装置の一例を示す図である。
【図１２】 図１１に示した被覆装置の異なる作動状態を示す図である。
【図１３】 本発明の被覆装置の他の例を示す図である。
【図１４】 図１３に示した被覆装置の異なる作動状態を示す図である。
【図１５】 比較例、実施例１及び実施例２の被覆ステントからの溶離速度の比較を示すグラフである。
【図１６】 実施例４ａ、４ｂ、５及び６の被覆ステントからの溶離速度の比較を示すグラフである。
【符号の説明】
２…被覆装置、４…ステント回転装置、６…噴霧装置、８…ステント、
１２…支持棒、１４…構造支持体、１６…第一の噴霧缶、１８…第二の噴霧缶、
２０…第一のディスペンサー、２２…第二の噴霧ディスペンサー、
２４’及び２４”…支持部材、２６及び２８…ガス供給手段。[0001]
BACKGROUND OF THE INVENTION
The present invention relates generally to drug release coatings for medical devices that are inserted or implanted into the body. More specifically, the present invention dissolves the polymer in a first solvent (solvent A) to form a polymer system and the drug in a second solvent (solvent B) to form a drug system. A method of applying a drug release coating to a medical device that dissolves.
[0002]
[Prior art and problems to be solved by the invention]
In conventional methods, a composition comprising a mixture of drug and polymer in a solvent is applied to the device to provide a substantially uniform layer of drug and polymer (ie, a layer in which the drug is substantially uniformly dispersed in the polymer). Was forming. Depending on the type of polymer and drug used, it was difficult to find a solvent common to these two components. In the absence of a common solvent for the drug and polymer, attempts have been made to refine the drug into small particles and suspend it in the polymer solution. However, miniaturization took time and sometimes lost the therapeutic properties desired for the drug. Accordingly, there is a need for a method for easily obtaining both drug and polymer solutions to obtain a drug release coating for medical devices. There is also a need for a method of applying a drug / polymer coating without the drug and polymer binding in a common solution or suspension.
[0003]
Means for Solving the Problem and Embodiment of the Invention
The methods described below are generally applied to implantable prostheses, particularly expandable prostheses such as balloon expandable stents and self-expanding stents. A stent coated according to the present invention is, for example, plastically deformable or self-expanding. In certain embodiments, the method does not require miniaturization before the drug is applied to the stent. In other embodiments, drug particles can be used. The present invention can also be used where there is no compatible solvent common to the polymer and drug.
[0004]
The present invention relates generally to a method of applying a drug and a polymer-containing drug release coating such that the drug is distributed substantially uniformly throughout the polymer. The polymer can be dissolved in a first solvent (solvent A) to form a polymer system that is substantially free of biologically active material (eg, less than about 1% by weight of the polymer) and the drug can be dissolved in a second solvent ( It can be dissolved in solvent B) to form a drug system that is substantially free of polymer (eg, less than about 1% by weight of the drug). The solvent B may be the same as or different from the solvent A. If the drug is very insoluble in the polymer solution and no common solvent can be found for both the drug and the polymer, different solvents are generally used. By applying the polymer system and drug system separately to the medical device, the method creates a polymer-drug complex, ie, a drug distribution throughout the polymer network. Such a complex can be substantially uniform. In the method of the present invention, it is not necessary to refine the drug before mixing it with the polymer to form a drug-polymer complex. This method provides a coating or layer comprising the drug and polymer complex, but eliminates the need to mix the drug and polymer in one solution prior to applying the coating to the device.
[0005]
The coating can be applied to devices, particularly stents, by spraying the polymer and drug systems separately. Methods for coating stents are disclosed in US patent application Ser. Nos. 08 / 424,884; 08 / 526,273; and 08 / 663,490. These references are hereby incorporated by reference in their entirety for all purposes. The coating of the present invention can be accomplished by spraying the polymer and drug system sequentially or simultaneously, as described in detail below.
[0006]
Instead of applying the coating by spraying, the coating can also be disposed on the medical device by dipping. This coating application method may be particularly useful for devices that cannot be spray coated. Such devices include, but are not limited to, the inner lumen of a stent graft. The coating may also be applied using a combination of spraying and dipping.
[0007]
Multi-step coatings may be applied depending on the desired coating thickness. Depending on the volatility of the solvent, a waiting time may be required during the spraying or dipping process, or heat may be applied by a heating gun, heating lamp or heating chamber to promote evaporation of the solvent. Good.
[0008]
In certain embodiments, the drug need not be dissolved in solvent B. The microparticles can be mixed, preferably suspended, in a solvent, and the coating applied as described herein. In some cases, three or more systems can be used. For example, if the third system solvent is compatible with a polymer matrix or a third spray or immersion system containing a second eluting material such as a drug, it contains pure solvent A or B The third spraying or dipping system can smooth the coated surface. Polyethylene glycol, sugar, salt in a solvent (which may be the same as or different from solvent A or B) can be applied to the stent. Drug emitters obtained using two or more drugs can release individual drugs simultaneously or sequentially.
[0009]
A suitable sequence according to the invention may be application of polymer solution, application of drug solution and application of pure solvent. Alternatively, this sequence may be application by spraying or dipping the polymer solution, application of the solvent, and application of the drug solution or suspension. Or this order may be three parallel sprays. The number of times in each operation may be 1/2, 1, 2, or more. Those skilled in the art will find many combinations for coating sequence and order for two or more coating systems without departing from the inventive concept. The coating system may be manual or automated to achieve various combinations.
[0010]
Suitable polymers for the present invention are preferably hydrophobic biostable elastomeric materials that do not degrade and minimize tissue rejection. Furthermore, the material is preferably such that it is encapsulated by tissue near the site of stent implantation. Suitable polymers for such coatings include silicones (eg, polysiloxanes and substituted polysiloxanes), polyurethanes (including polycarbonate urethanes), general thermoplastic elastomers, ethylene vinyl acetate copolymers, polyolefin elastomers, EPDM rubbers And polyamide elastomer. The above materials are considered hydrophobic with respect to the environment contemplated by the present invention.
[0011]
Non-limiting examples of other polymers suitable for use in the present invention include bioabsorbable polymers such as, for example, polylactic acid, polyglycolic acid, polycaprolactone, polylactic acid-polyethylene oxide copolymer, and cellulose. . Examples of other non-limiting polymers suitable for use in the present invention also include biostable plastic materials such as acrylic acid and its derivatives, nylon and polyester.
[0012]
Non-limiting examples of drugs used in the present invention include antitrobotics, anticoagulants, antiplatelet agents, thrombolytic agents, antiproliferative agents, anti-inflammatory agents, hyperplasia inhibitors, smooth muscle cell inhibitors It includes healthy neovascular intimal tissue formation promoters including agents, antibiotics, growth factors, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters and endothelial cell regeneration. Positive effects result from the inhibition of specific cells (eg smooth muscle cells) or tissue formation (eg fiber muscle tissue), activation of different cell migration (eg endothelial cells) and tissue formation (new intimal tissue).
[0013]
The drug used in the present invention may or may not be miniaturized. When the drug is not miniaturized, the particle size of the drug can be about 10 μm or more. When the drug is miniaturized, the particle diameter of the drug is preferably 5 to 12 μm, more preferably about 5 μm.
[0014]
Devices suitable for the present invention include catheters, shunts, stents (eg, self-expandable or balloon expandable vascular or non-vascular stents), heart valves, grafts, and artificial organs and prostheses. Limitedly included. These devices may have a polymer, metal or ceramic surface.
[0015]
Preferred materials for constructing a stent, particularly a braided shunt as shown in FIG. 10, are stainless steel, tantalum, titanium alloys such as Nitinol (a nickel and titanium heat storage alloy material), as described in US Pat. No. 5,630,840. And other metals such as cobalt-chromium-nickel alloys such as Elgiloy and Phynox. Bioabsorbable materials can also be used to form stent structures, such as polylactic acid. Further details of construction and other details of the stent itself are described in U.S. Patent Nos. 4,655,771, 4,954,126 and 5,061,275, all of which are incorporated herein by reference. To do.
[0016]
Solvents that can be used in the present invention are preferably compatible when mixed with polymers and drugs. For example, the polymer is preferably sufficiently soluble in the solvent when mixed, and the drug is preferably sufficiently soluble in the solvent when mixed. However, some embodiments of the invention also include particulate drugs such as heparin mixed in a solvent. When the drug is in particulate form, the drug is preferably suspended in a solvent. Non-limiting examples of solvents that can be used in the present invention include tetrahydrofuran, methanol, methyl ethyl ketone, chloroform, methylene chloride, acetonitrile and water.
[0017]
【Example】
The following examples describe embodiments of the invention in which the coating is applied to a medical device by spray coating (Comparative Examples and Examples 1-3) or dip coating (Examples 4-6).
[0018]
(Comparative example)
A mixture of silicone and xylene (approximately 34% solids weight; Applied Silicone Corporation) was weighed to calculate the solid silicone content. A ratio of Wdex / Wsilicone solid = 0.1) was used for the production. Here, “dex” or “DEX” is dexamethasone (Upjohn; US Pharmacopoeia dexamethasone; CAS registration number 50-02-2). The volume of tetrahydrofuran (THF) used (HLPC purity; Aldrich or EM Science) was measured by multiplying the weight of the solid silicone by 20. DEX was first dissolved in THF and then transferred to the silicone-xylene mixture. Crosslinker was added and the solution mixed well. The knitted stent was sprayed several times with a uniform solution to coat the expanded stent. The coated stent was transferred to a convection oven and treated at 150 ° C. for 45 minutes. Next, it was treated with argon gas plasma by the method described in US Patent Application No. 08 / 841,747. The results are shown in FIGS. Figures 1 and 4 are photographs of the coating in an unstressed state, i.e., before the stent is expanded or contracted. FIG. 5 is a photograph of the coating after the coated stent is mechanically stressed, ie, after the stent is contracted and expanded.
[0019]
Example 1
A 5% (w / w) solid silicone solution in THF was prepared by adding the required THF and crosslinker into the silicone mixture. Separately, a 0.5% silicone solution in THF was prepared by adding THF into a DEX containing beaker. The ratio of Wdex / Wsilicone solid was 0.1. A badger 150-4 spray system was used with two reservoirs containing two different solutions. Covering the expanded stent was completed by spraying one cycle of silicone solution, short latency (about 30 seconds) and one cycle of DEX, short latency (about 30 seconds), and repeated spraying operations. The last spray cycle was a silicone solution. Approximately 30 cycles of each were applied to obtain a coating thickness of 30 microns. The number of spray cycles used was dependent on solution viscosity, droplet size and flow rate. The coated stent was then transferred to a convection oven and treated at 150 ° C. for 45 minutes. Furthermore, it processed with argon gas plasma. The results are shown in FIGS. Figures 2 and 6 are photographs of the coating in an unstressed state. FIG. 7 is a photograph of the coating after the coated stent is mechanically stressed.
[0020]
(Example 2)
The method used to produce this example is similar to the method used in Example 1 except that DEX was dissolved in methanol, a poor solvent for silicone. During production, the ratio of Wdex / Wsilicone solid was kept at 0.1. The results are shown in FIGS. 3 and 8 are photographs of the coating in the unstressed state. FIG. 9 is a photograph of the coating after the coated stent has been mechanically stressed, ie expanded and contracted.
[0021]
(Example 3)
The coated stents produced in Comparative Example, Example 1 and Example 2 were cut into 2 cm sections and into 100 ml of a mixture of polyethylene glycol (molecular weight = 400, Aldorich) and water (40/60, v / v). I put it in. This solution was changed frequently each time the solution was sampled. The DEX concentration was analyzed using a Shimadzu high performance liquid chromatography instrument operating at a wavelength of 254 nm with a UV detector. A C-8 column was used for the analysis. Table 1 and FIG. 15 show the DEX release data over one month for the coated stent. The three products of Comparative Example, Example 1 and Example 2 all extended drug release and had similar release profiles.
[0022]
[Table 1]
Figure 0004044190
[0023]
Embodiments of the present invention including spray coating are described step by step in FIGS. The drug release coating coating device 2 includes a stent rotating device 4 and a spraying device 6.
[0024]
The stent 8 is mounted on the stent rotation device 4 by pinching it at both ends of the support members 24 ′, 24 ″, typically with a mouth clamp, preferably the stent 8 is at least partially expanded or fully When sandwiched in an expanded state, the interior leaves a space where the spray coating adheres to the exterior and interior surfaces of the stent 8. The rod members 24 ', 24 "do not cross the interior of the stent 8. . The motor 10 rotates the stent 8 by rotating the rod members 24 ′ and 24 ″. The support rod 12 supports the stent rotating device 4.
[0025]
The spray device 6 has a structural support 14 on which a first spray can 16 and a second can 18 are mounted. The first spray can 16 communicates with the first spray dispenser 20, and the second spray can 16 communicates with the second spray dispenser 22. The gas supply means 26, 28 are connected to a spraying device to drive the polymer solution and the drug solution.
[0026]
The first and second spray cans 16, 18 can be mounted on a structural support 14 on a track (not shown) and can be translated back and forth in the longitudinal direction. In simple cases, the hand can be actuated as a support 14. In this embodiment, the cans 16, 18 are fixed at a predetermined distance from each other and move together equidistantly. The white arrows in FIG. 11 indicate the cans 16 and 18 before moving to the left. Once the spray dispensers 20, 22 face the stent 8, spraying is started. The black arrow in FIG. 11 shows the cans 16, 18 starting to return to the right and again spraying the dispensers 20, 22 against the stent. This operation can be repeated as many times as desired.
[0027]
In this embodiment, the first spray can 16 may contain a polymer in the solvent but no drug, while the second spray can 18 contains the drug in the solvent. It can be free of polymer and vice versa.
[0028]
Figures 13 and 14 sequentially illustrate other embodiments of the present invention. The reference numbers in this embodiment have the same meaning as used in the embodiment shown in FIGS.
[0029]
The first and second spray cans 16, 18 can be mounted on the structural support 14 on two tracks (not shown) and can be translated in the longitudinal direction. In this embodiment, the cans 16, 18 are capable of translational movement independently of each other. In FIG. 13, the black arrow indicates the first can 16 that moves leftward to spray the stent, and the white arrow indicates the second can 18 that is waiting to move leftward in the rest position. Show. The first can 16 continues to move to the left and then stops beyond the stent and into a rest position (not shown). Next, as shown in FIG. 14, the second can 18 moves to the left to spray the stent and then rests on the left of the stent. Thereafter, the first can 16 moves to the right, the second can 18 continues, and the process is repeated as desired.
[0030]
Another method according to the present invention is that the second can 18 rests over the stent while the first can 16 translates back and forth, and then the second can translates back and forth. Including a stroke in which the first can rests beyond the stunt. Other non-limiting variations include having cans 16 and 18 that move at the same time but are spaced apart from each other, or have cans 16 and 18 that intersect the cross during spraying.
[0031]
In addition to spray coating, the coatings of the present invention can be applied by immersing the medical device in 1) a polymer dissolved in a first solvent and 2) a drug dissolved in a second solvent. The device can be repeatedly immersed in the polymer and drug solution until a coating of the desired thickness is obtained. In general, depending on the relative solubility of the solvent in the polymer and drug, the drug is recrystallized or redistributed and the polymer shrinks and swells in successive immersion steps. A certain process was employed to ensure coating uniformity in the instrument. These steps include, but are not limited to: That is, select a solvent with a low viscosity coefficient, select the polymer above its entanglement molecular weight so that the inner polymer layer swells but does not dissolve easily, blow dry the coating after each immersion, Coating horizontally, rotating the instrument during drying, and reducing coating time.
[0032]
The following examples illustrate embodiments of the present invention in which production by immersion is performed.
[0033]
Example 4
A silicone dispersion containing 35% solids (Applied Silicone Corporation) (# 40000) (15 grams) was weighed. Dexamethasone (DEX) (Upjohn, Lot # 719kT) (0.52 grams) was dissolved in 15 ml of tetrahydrofuran (THF). The drug solution was added to the silicone dispersion and stirred until a homogeneous solution was obtained.
[0034]
The stent graft (Example 4a) was immersed in this solution and air-dried in a horizontal position. The coating weight of this sample was 10.8 mg / cm 2 . Due to gravity, the coating became uneven. In order to obtain a more uniform coating, after immersing in the solution, the second stent graft (Example 4b) was rotated horizontally with air drying. The coating weight of this sample was 13.5 mg / cm 2 . After standing at room temperature for about 1.5 hours, the coated sample was treated in an oven at 150 ° C. for 1 hour.
[0035]
The graft was cut into 2 cm pieces and the release rate was examined by immersing in a 25/75 v / v aqueous solution of polyethylene glycol (PEG) (molecular weight = 400; JTBaker). The solution was sampled periodically and replaced with fresh solution. The amount of DEX released was measured using a C8 column (Phase Separation Ltd) with a mobile phase of acetonitrile / water (1: 1, v / v) at a flow rate of 1 ml / min using a UV detector at a wavelength of 254 nm. Quantification was performed by high performance liquid chromatography (HPLC) from Shimadzu Corporation. The release rates for these two samples are shown in Table 2. These data indicate that the coated sample has extended drug release (see FIG. 16).
[0036]
[Table 2]
Figure 0004044190
[0037]
A silicone dispersion containing 4% silicone in THF was made. A 10% DEX solution in THF was also made. The stent graft was first immersed in a silicone solution and dried while rotating for at least 1 minute. The stent was immersed in a DEX / THF solution and rotated for at least 1 minute to dry the stent. This soaking and drying operation was repeated about 20 times. The last soak was in a silicone solution. After standing at room temperature for about 1.5 hours, the coated sample was processed in an oven at 150 ° C. for 1 hour.
[0038]
Similar to the stents of Examples 4a and 4b, this sample was also cut into 2 cm pieces and examined for release rate by the method used in Examples 4a and 4b. The release rate in Example 5 is shown in Table 2 and FIG. These data indicate that the coated sample has extended drug release.
[0039]
(Example 6)
The silicone dispersion liquid of Example 5 was produced. A 10% solution of DEX in methanol (MeOH) was also made, which is a poor solvent for silicone and therefore incompatible with silicone. The stent graft was coated by the method used to make Example 5. This sample was cut into 2 cm pieces and the release rate was examined by the method used in Examples 4a and 4b. The release rate of Example 6 is shown in Table 2. These data show that the coated sample has extended drug release, but this sample had faster initial drug elution compared to those of Examples 4a, 4b and 5. (See FIG. 16).
[0040]
What has been described herein is for illustrative purposes only and not for purposes of limitation. Changes and modifications may be made to the embodiments described and are within the scope of the invention. Furthermore, obvious changes, modifications or variations will also be made by those skilled in the art.
[Brief description of the drawings]
FIG. 1 is a scanning electron micrograph showing a coated stent of a comparative example.
2 is a scanning electron micrograph showing the coated stent of Example 1. FIG.
3 is a scanning electron micrograph showing the coated stent of Example 2. FIG.
FIG. 4 is a scanning electron micrograph showing a comparative coated stent in an unstressed state.
FIG. 5 is a scanning electron micrograph showing a coated stent of a comparative example in a state after stress.
FIG. 6 is a scanning electron micrograph showing the coated stent of Example 1 in an unstressed state.
FIG. 7 is a scanning electron micrograph showing the coated stent of Example 1 in a state after stress.
FIG. 8 is a scanning electron micrograph showing the coated stent of Example 2 in an unstressed state.
FIG. 9 is a scanning electron micrograph showing the coated stent of Example 2 in a state after stress.
FIG. 10 is a perspective view showing an example of a stent before coating.
FIG. 11 is a diagram showing an example of a coating apparatus according to the present invention.
12 is a diagram showing different operating states of the coating apparatus shown in FIG.
FIG. 13 is a view showing another example of the coating apparatus of the present invention.
FIG. 14 is a diagram showing different operating states of the coating apparatus shown in FIG.
FIG. 15 is a graph showing a comparison of elution rates from the coated stents of Comparative Example, Example 1 and Example 2.
FIG. 16 is a graph showing a comparison of elution rates from the coated stents of Examples 4a, 4b, 5 and 6.
[Explanation of symbols]
2 ... coating device, 4 ... stent rotating device, 6 ... spraying device, 8 ... stent,
12 ... support rod, 14 ... structural support, 16 ... first spray can, 18 ... second spray can,
20 ... first dispenser, 22 ... second spray dispenser,
24 'and 24 "... support members, 26 and 28 ... gas supply means.

Claims (23)

患者の体内へ挿入または移植するための少なくとも１つの部材を具備し、該部材は患者の体組織に露出され、かつ該部材表面の少なくとも一部は、少なくとも１つの生物学的活性物質を放出するために被覆されている医療器具の製造方法であって、ａ）ポリマー及び第一の溶媒からなり、生物学的活性物質を実質的に含まず且つシリコーンポリマーを含んでなるポリマー系を前記部材表面に適用し；かつｂ）生物学的活性物質と第二の溶媒からなり、ポリマーを実質的に含まない薬物系を前記部材表面に適用することからなり、前記部材表面にポリマーと生物学的活性物質の複合体を形成し、
前記ポリマーと生物学的活性物質の複合体が実質的に均一であり、
前記ポリマー系と薬物系とを別々に同時に前記表面に適用するか、又は前記ポリマー系と薬物系とを別々に逐次的に前記表面に適用することを特徴とする方法。At least one member for insertion or implantation into a patient's body, the member being exposed to the patient's body tissue, and at least a portion of the member surface releasing at least one biologically active substance A method for producing a medical device coated for: a) a polymer system comprising a polymer and a first solvent, substantially free of biologically active material and comprising a silicone polymer, And b) applying a drug system comprising a biologically active substance and a second solvent, substantially free of polymer, to the member surface, wherein the polymer and biological activity are applied to the member surface. Forming a complex of substances,
The polymer and biologically active agent complex is substantially homogeneous;
Applying the polymer system and drug system separately and simultaneously to the surface, or applying the polymer system and drug system separately and sequentially to the surface. 前記工程ａ）とｂ）とが反復される請求項１記載の方法。  The method of claim 1 wherein steps a) and b) are repeated. 前記医療器具がステントである請求項１記載の方法。  The method of claim 1, wherein the medical device is a stent. 前記ステントが、自己拡張ステントである請求項１記載の方法。  The method of claim 1, wherein the stent is a self-expanding stent. 前記第一の溶媒と第二の溶媒が同一の溶媒である請求項１記載の方法。  The method of claim 1, wherein the first solvent and the second solvent are the same solvent. 前記第一の溶媒と第二の溶媒が異なる溶媒である請求項１記載の方法。  The method of claim 1, wherein the first solvent and the second solvent are different solvents. 前記ポリマーが疎水性の生体安定性エラストマーである請求項１記載の方法。  The method of claim 1, wherein the polymer is a hydrophobic biostable elastomer. 前記エラストマーが、シリコーン、ポリウレタン、熱可塑性エラストマー、エチレンビニルアセテート共重合体、ポリオレフィンエラストマー、ＥＰＤＭゴム及びポリアミドエラストマーよりなる群から選ばれるものである請求項１記載の方法。  The method according to claim 1, wherein the elastomer is selected from the group consisting of silicone, polyurethane, thermoplastic elastomer, ethylene vinyl acetate copolymer, polyolefin elastomer, EPDM rubber, and polyamide elastomer. 前記生物学的活性物質が、アンチトロボティックス、抗凝固剤、抗血小板剤、血栓溶解剤、抗増殖剤、抗炎症剤、過形成阻害剤、平滑筋細胞阻害剤、抗生物質、成長因子、成長因子阻害剤、細胞接着阻害剤、細胞接着促進剤および健常新血管内膜組織形成促進剤よりなる群から選ばれるものである請求項１記載の方法。  Antibiotics, anticoagulants, antiplatelets, thrombolytic agents, antiproliferative agents, anti-inflammatory agents, hyperplasia inhibitors, smooth muscle cell inhibitors, antibiotics, growth factors, The method according to claim 1, wherein the method is selected from the group consisting of a growth factor inhibitor, a cell adhesion inhibitor, a cell adhesion promoter, and a healthy new intimal tissue formation promoter. 前記ポリマー系または薬物系が噴霧被覆によって適用される請求項１記載の方法。  The method of claim 1, wherein the polymer system or drug system is applied by spray coating. 前記ポリマー系または薬物系が浸漬によって適用される請求項１記載の方法。  The method of claim 1, wherein the polymer system or drug system is applied by dipping. 前記ポリマー系と薬物系とが噴霧被覆によって適用される、請求項１記載の医療器具の製造方法。 The method of manufacturing a medical device according to claim 1, wherein the polymer system and the drug system are applied by spray coating . 前記薬物系の適用の前に、第一の溶媒の一部を蒸発させることを更に含む請求項１記載の方法。 The method of claim 1, further comprising evaporating a portion of the first solvent prior to application of the drug system. 前記生物学的活性物質が第二の溶媒に溶解されている請求項１記載の方法。  The method of claim 1, wherein the biologically active substance is dissolved in a second solvent. 前記生物学的活性物質が第二の溶媒に懸濁されている請求項１記載の方法。  The method of claim 1, wherein the biologically active substance is suspended in a second solvent. 溶媒を表面に適用することを更に含む請求項１の方法。  The method of claim 1, further comprising applying a solvent to the surface. 第二の生物学的活性物質からなりポリマーを実質的に含まない第二の薬物系を表面に適用することを更に含む請求項１記載の方法。  The method of claim 1, further comprising applying a second drug system comprising a second biologically active material and substantially free of polymer to the surface. 被覆を有する医療器具８の表面の少なくとも一部を被覆する装置２であって、
ａ）装置２に器具８をマウントするための少なくとも１つの支持部材２４を具備するマウント装置４、及び、
ｂ）器具８の表面に噴霧するように該マウント装置４に配設した噴霧装置６であって：
ｉ）構造支持体１４、及び、
ｉｉ）該構造支持体１４上で可動的に保持され、各々が、第一の噴霧ディスペンサー２０及び第二の噴霧ディスペンサー２２と連通した第一および第二の噴霧缶１６、１８を具備する噴霧装置６を具備する被覆装置であって、請求項１２に記載の医療器具の製造方法に用いることを特徴とする被覆装置。A device 2 for coating at least part of the surface of a medical device 8 having a coating,
a) a mounting device 4 comprising at least one support member 24 for mounting the instrument 8 on the device 2, and
b) A spraying device 6 arranged on the mounting device 4 to spray on the surface of the instrument 8:
i) the structural support 14, and
ii) a spraying device comprising first and second spray cans 16, 18 movably held on said structural support 14, each in communication with a first spray dispenser 20 and a second spray dispenser 22. A coating apparatus comprising: the medical apparatus according to claim 12 . 前記第一と第二の噴霧ディスペンサー２０、２２に各々接続されたガス供給手段２６、２８を具備する請求項１８記載の装置。19. Apparatus according to claim 18 , comprising gas supply means (26, 28) connected to the first and second spray dispensers (20, 22), respectively. 前記第一及び第二の噴霧缶１６、１８が、互いに予め決められた距離をおいて固定されている請求項１８記載の装置。19. The apparatus of claim 18, wherein the first and second spray cans 16, 18 are fixed at a predetermined distance from each other. 前記第一及び第二の噴霧缶１６、１８が、互いに独立して移動可能とされた請求項１８記載の装置。19. The apparatus of claim 18, wherein the first and second spray cans 16, 18 are movable independently of each other. 前記第一及び第二の噴霧缶１６、１８が、該噴霧缶１６、１８が互いに入れ違いに移動できるように前記構造支持体１４に可動に保持された請求項１８記載の装置。Said first and second spray cans 16, 18, The apparatus of claim 18, wherein the該噴Kirikan 16, 18 is moveably retained in the structure supporting member 14 so as to be movable in Irechigai each other. 前記支持部材２４を回転させるモーター１０を更に具備する請求項１８記載の装置。The apparatus of claim 18 , further comprising a motor that rotates the support member.
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